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The immune system plays a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades, and its expression is upregulated in Alzheimer's disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta (Aβ) plaques in the brain. Despite evidence linking P2RX7 to AD, the mechanisms by which it shapes microglial responses and contributes to AD remain poorly defined. Here, we utilize a human monocyte-derived microglia-like cell model (MDMi) to interrogate P2RX7 activation and downstream consequences on microglial function. Specifically, we measured IL1β and IL18 production and Aβ1–42 uptake following ATP-induced P2RX7 activation. Our results show that ATP-stimulation of MDMi triggers upregulation of IL1β and IL18 expression, which is blocked with the A740003 P2RX7 antagonist. Elevated extracellular ATP also impaired Aβ1–42 uptake, an effect reversed by P2RX7 inhibition with A740003. In addition, pretreatment of MDMi with IL-1Ra limited ATP-driven IL1β and IL18 gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Critically, analysis of postmortem human brain revealed that P2RX7 expression significantly mediated the association between IL18 , but not IL1β , and multiple AD traits, including amyloid load, tau tangle density, global AD pathology burden, cortical and neocortical Lewy bodies, cognitive decline, and clinical dementia. Consistent with these findings, in our MDMi model, P2RX7 gene expression correlated with IL18 but not IL1β . Together, these findings highlight P2RX7 as a critical integrator of extracellular danger signals and microglial immune function, underscoring its potential as a therapeutic target in neurodegeneration. • P2RX7 is a direct driver of IL-1b and IL-18 transcription and secretion in a model of human microglia. • ATP-activation of P2RX7 impairs amyloid phagocytosis in a model of human microglia. • Inhibition of either P2RX7 or IL-1R abrogates these ATP-induced cytokine and phagocytosis effects. • Human brain P2RX7 gene expression uniquely mediates IL18's association with Alzheimer's traits.
Heavener et al. (2025) studied this question.